MXPA06012348A

MXPA06012348A - Methods of diminishing co-abuse potential.

Info

Publication number: MXPA06012348A
Application number: MXPA06012348A
Authority: MX
Inventors: Vikram Khetani; Herbert Faleck
Original assignee: Celgene Corp
Priority date: 2004-04-26
Filing date: 2005-04-26
Publication date: 2007-04-19
Also published as: IL178683A0; EP1755393A4; US20120136028A1; CN1946292B; EP1755393A2; US20130158073A1; WO2005105087A2; US20090062336A1; JP2007534763A; AU2005237538A1; CA2564604A1; ZA200608838B; BRPI0510325A; KR20070004127A; US20050239830A1; WO2005105087A3; AU2005237538B2; CN1946292A; KR20130041359A; NZ550585A

Abstract

Methods of diminishing or eliminating the co-abuse of a methylphenidate drug comprising identifying a patient or patient group suspected or likely to abuse said methylphenidate drug in combination with a substance known or suspected to give rise to l-ethylphenidate or psychotropic effect when ingested in the combination and making available to said patent or patient group said methylphenidate drug substantially free of l-threo methylphenidate.

Description

METHODS TO ATTENUATE THE POTENTIAL OF CO-ABUSE FIELD OF THE INVENTION This invention relates to methods for reducing or eliminating the co-abuse of methylphenidate drugs with substances that can be abused such as alcohol, cocaine, opioids or nicotine. Methods for reducing the adverse effects associated with the co-administration of drugs and fenidate substances such as alcohol or other active central nervous system agents in patients undergoing treatment for ADHD (Attention Deficit Hyperactivity Disorder) are also described. Attention Deficit) and other conditions in which fenidate products are administered.

BACKGROUND OF THE INVENTION Methylphenidate is known to be co-administered with alcohol and other substances by those who abuse substances. In a recent study, three percent of college students abuse methylphenidate. According to Teter, et al., Pharmacotherapy, 2003; 23: 609-17, ninety-eight percent of these illicit users of methylphenidate are also drinking sprees. Barrett, et al., J. Clin Psychopharmacol, 2002; 22: 633-4, describes that the oral mode of administration of methylphenidate is becoming more common than intravenous or intranasal modes when used concomitantly with alcohol. There are some theories for the co-abuse of methylphenidate and alcohol. They include the alteration and increase of psychotropic effects, production of desirable effects characterized by an increase in euphoria and energy as well as an attenuated sense of drunkenness, and an experience compared with "low quality cocaine" or "dietary coca" . Another theory is that children who grow up with the habit of taking stimulants for their ADH D are more likely to take illegal stimulants such as cocaine or methamphetamines. There is a need for a treatment that does not generate the additive euphoric effects experienced when methylphenidate is co-abused with other stimulants. There is also a need for a method to reduce the adverse effects associated with the co-administration of drug and fenidate substances such as alcohol, or other active agents of the central nervous system in patients undergoing treatment for ADH D. According to Sabri , et al., Alcohol and Alcoholism, 2003; 38: 352-6, alcohol dependence in children with ADH D begins at an early age and is resistant to treatment. The abuse of co-morbid substances is more prevalent in patients with ADH D. Adults with ADH D are known to have co-morbid alcohol problems and an elevated risk of substance use disorders. Patients who use fenidate drugs to treat fatigue related to cancer and cognitive disorders also have the potential for co-abuse of fenidate. These patients are more likely to take medications such as opioid analgesics for pain. These patients are also more likely to co-administer methylphenidate and alcohol. A safer drug is required for these patients compared to other formulations containing methylphenidate, particularly the racemic mixture. It has also been discovered that patients who use fenidate drugs as adjuvants for substances used to treat pain conditions include but are not limited to Complex Regional Pain Syndrome, low back pain, fibromyalgia, radiculopathy, peripheral neuropathy, for example, Diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia are more likely to take medications such as opioid analgesics for pain. These patients are also more likely to co-administer methylphenidate and alcohol. Patients who are treated for neurological or neuropsychiatric conditions include but are not limited to infarction, head trauma, and depression are more likely to co-administer methylphenidate and alcohol. Markowitz, et al., J. Clin. Psychopharmacol., 1 999; 1 9: 362-6, they discovered that ethylphenidate was detected as a new metabolite in the plasma after an overdose of methylphenidate with coingestion of alcohol. Many methylphenidate products such as Concerta®, Rítalin®, and Metadato® present a great potential for coabuse because methylphenidate is a metabolite of these products. Markowitz, et al., Drug Metabolism and Disposition, 2000; 28: 620-5 state that ethylphenidate was also detected in plasma and urine in human patients after co-administration of a single dose of methylphenidate and ethanol. Ethylphenidate is known to have a dopaminergic activity. Recently it was discovered by Thomson, et al. , 31st Annual Am. College of Clin. Pharmacol. Meeting Abstracts, 2002, that after the co-administration of racemic methylphenidate and ethanol, / -methylphenidate is enantioselectively transesterified to / -ethylphenidate. The metabolite of ethylphenidate was excreted in the urine basically as the / -isomer. Methylphenidate was basically excreted as the d-isomer. Ethylphenidate potentially contributes to the euphoric effects in co-abusers and the adverse effects in patients with ADH D, patients with cancer and patients with neurological and neuropsychiatric disorders. It is an object of the present invention to provide a means to treat patients who have a greater potential for co-abuse of methylphenidate with illicit drugs such as cocaine and methamphetamines. It is also an object of the present invention to reduce the potential adverse effects associated with the administration drug administration of fenidate and alcohol, opioids or other active agents of the central nervous system. Another object of the present invention is to reduce the adverse effects associated with the co-administration of phenytoin and alcohol drugs, opioids, nicotine, or other active agents of the central nervous system in patients who use fenidate drugs to treat fatigue related to the cancer and cognitive disorders. The threo racemate (pair of enantiomers) of methylphenidate is a mild stimulant of the central nervous system with pharmacological activity qualitatively similar to that of amphetamines. It has been postulated that there are undesirable side effects associated with the use of the dl-threo racemate of methylphenidate which include anorexia, weight loss, insomnia, dizziness and dysphoria. Also, the racemate is a substance controlled by the I I Program that produces an euphoric effect when administered intravenously or by inhalation or ingestion, and which consequently presents a high potential for abuse. Recently, it has been discovered that racemate can also lead to co-abuse of methylphenidate with other stimulants. Therefore, there is a need for treatments that administer the compositions that will not interact with col as racemic methylphenidate and that will not produce adverse effects.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides methods for reducing co-abuse of a methylphenidate drug with a substance that presumably causes / -ethylphenidate when ingested in combination with the methylphenidate drug comprising identifying a patient or group of patients. who allegedly abuse or are prone to abuse the combination and who provide the patient or group of patients with a methylphenidate drug substantially free of l-threo methylphenidate. The methylphenidate drug may comprise dexmethylphenidate. There are also methods for reducing co-abuse of the combination of a methylphenidate drug with an addictive substance which comprises identifying a patient or group of patients who allegedly abuse or who are prone to abuse the combination, and making themselves available to the patient. or group of patients a methylphenidate drug substantially free of l-threo methylphenidate. There are modalities where the substance that causes I-ethylphenidate can be ethyl alcohol. There are also modalities where the addictive substance can be cocaine or cocaine derivatives, an opioid, ethyl alcohol, an active agent of the CNS (Central Nervous System), or nicotine. It will be noted that the addictive substance can be known to produce a psychotropic effect. The drug can be made available to the patient orally, intravenously, parenterally, by an aerosol or gas suspension, or transdermally. These dosage forms may comprise up to about 10 mg, 5 mg, or 3 mg of a methylphenidate drug which is substantially free of l-threo methylphenidate. The methods may comprise from about 0. 1 mg to about 1000 mg of said methylphenidate drug substantially free of l-threo methylphenidate. It is sometimes suspected that patients have ADD or ADH D. There are also methods to reduce the co-abuse of a methylphenidate drug with a substance that presumably causes / -ethylphenidate when ingested in combination with the methylphenidate drug that comprises identifying a patient or group of patients who presumably abuse or are prone to abuse the combination and decrease the amount of / -ethylphenidate produced by the ingestion of the combination by making available to said patient or group of patients a free methylphenidate drug. l-threo methylphenidate.

DETAILED DESCRIPTION OF THE PREFERRED MODALI DAD In accordance with the present invention, methods for attenuating drug co-abuse of methylphenidate with an addictive substance or from which it can be abused are provided. One preferred modality comprises identifying a patient or group of patients who allegedly abuse or who are prone to abuse a methylphenidate drug in combination with a known substance or that presumably gives rise to / -ethylphenidate when ingested in the combination and making said methylphenidate drug substantially free of l-threo methylphenidate available to said patient or group of patients. Some embodiments of the present invention relate to a methylphenidate drug composition that reduces or eliminates the potential for co-abuse or co-abuse itself. The co-administration of the drug methylphenidate and other substances that can be abused, such as but not restricted to alcohol, cocaine, or nicotine, does not produce the same psychotropic effects as racemic methylphenidate or amphetamines. As such, those who abuse the substances and will probably co-abuse the drug formulations containing the compositions described herein. Methylphenidate exists as four separate optical isomers as explained below: l-treo d-erythro d-treo l-erítro where R2 is phenyl. The pharmaceutically acceptable salts are generally administered clinically. Other fenidate drugs, which may also be administered according to the invention, include those in which the methyl group in the above structures is replaced by the C2-C alkyl and R2 is optionally substituted with C? -C4 alkyl. Clinically, the pair of threo enantiomers of methylphenidate hydrochloride is generally administered for the treatment of ADD and ADH D. The hydrochloride salt is commonly referred to simply as "methylphenidate". Unless otherwise indicated, the term "methylphenidate" is used extensively herein to include methylphenidate and pharmaceutically acceptable salts thereof, including methylphenidate hydrochloride. Although d / -r? Eo-methylphenidate is generally used therapeutically, this racemate includes the / isomer that apparently makes no significant contribution to the pharmacological effectiveness of the drug, but probably contributes to the associated side effects. Consequently, it is desirable to administer a substantially free dosage form of the / isomer. It has now been discovered that similar dosage forms can be used to attenuate the co-abuse potential of methylphenidate. In a further aspect, the present invention relates to the reduction of the CNS adverse effects of phenytoic drugs, exacerbated by substances such as, but not restricted to alcohol, opioid analgesics, nicotine, and other active agents of the central nervous system. More specifically, the drug formulation containing dexmethylphenidate, also known as methylphenidate which is substantially free of the / -isomer, is a preferred mode for treating patients with ADH D, who have a greater dependence on co-morbid alcohol and an increased risk of suffering from substance use than the general population. These patients are prone to consume alcohol even if they are under medication for ADH D. In addition, dexmethylphenidate is a preferred way to treat patients with cancer-related fatigue and cognitive conditions or other neurological or neuropsychiatric conditions that are more likely to consume alcohol and co-administering other medications such as opioid analgesics to relieve pain or other active agents of the central nervous system. Drug formulations of some embodiments of the present invention are substantially free of l-threo-methylphenidate and er / methyl-methylphenidate. The reduction of the co-abuse potential and the adverse effects can be attributed to the absence of the / -fiber-isomer in some modalities. The embodiments of the present invention have attenuated the potential for co-abuse and reduced adverse effects when co-administered with alcohol. It will be noted that there may be various theories that explain this result. One may be that the dexmethylphenidate formulation is substantially free of / -rhemethylphenidate and er / rr-methylphenidate. The drug formulations of the present invention do not produce the euphoric effects when they are co-abused with other addictive substances. A feature of the present invention is that the drug does not produce adverse effects in patients with ADH D or cancer who are also consuming alcohol or taking medications such as opioid analgesics. The co-administration of racemic metaphenidate and alcohol is known to produce psychotropic effects in humans. These adverse effects are potentially due to the production of the metabolite of / -ethylphenidate. An advantage of the present invention may be that the co-administration of dexmethylphenidate and alcohol will not produce these effects. A difference between some embodiments of the present invention and similar methods of reducing co-abuse with racemic methylphenidate and alcohol is that dexmethylphenidate is substantially free of the / -isomer. Therefore, the metabolite of / -ethylphenidate is not formed. The / -ethylphenidate is potentially responsible for the euphoric and adverse effects. The methods of the present invention can have a certain number of particular modalities for the specific needs of the person skilled in the art. In some methods, the drug provided or administered to the patient comprises a pharmaceutical unit dosage form which may have up to about 10 mg of dexmethylphenidate substantially free of l-threo methylphenidate. In other modalities, the drug comprises up to about 5 mg of dexmethylphenidate or up to about 3 mg of said dexmethylphenidate both substantially free of l-threo methylphenidate. In some other embodiments, the unit dosage form may vary from about 0.1 mg to about 1000 mg or more of dexmethylphenidate, and they also achieve an attenuation of the coabuse effect. The dosage forms of the present invention can be administered or made available to the patient under treatment orally, intravenously, parenterally, aerosol or suspension in gas, or transdermally. Oral administration can be by capsule or tablets.

EXAM PLO Patients: Eight Sprague-Dawley male rats are maintained on a restricted feeding regimen to maintain their weights in the range of 375-425 grams. Apparatus: the experimental sessions are carried out in commercial chambers, with two levers, which operate with rats contained within cubicles to attenuate light and sound. The cameras are equipped with tablet dispensers for 45 mg tablets. A stimulus light signals when the session is in progress. Training: Patients who have already been trained to discriminate ethanol / cocaine co-administered from brine are used. The rats have been trained to press a lever for food reinforcement during 30-minute sessions per day. During training, each lever is associated either with 0.75 mg / kg of cocaine in 10% w / v ethanol or in brine injections (ie 1, 5 pre-sessions of minutes). Patients learn to discriminate which injection is applied in order to determine what is the correct lever for each session. Training continues until patients begin each session on the corrected lever for four consecutive sessions. Test: Generalization tests are carried out twice a week. Between the test sessions, the animals undergo a training phase with ethanol / cocaine and injections of brine. In test sessions, the response to both levers is reinforced. The tests with 0.75 mg / kg of cocaine in ethanol at 10% w / v and brine are carried out at the beginning of each determination of curves due to the effect of doses. A complete curve by dose effect is obtained for each test drug. The test injections are given 1 5 minutes i. p. before the start of the testing session. The tests are carried out with the following three drugs co-administered with ethanol: HCl of dexmethylphenidate (d-MPH) at 10% w / v, HCl of d, l-methylphenidate (d, l-M PH), and cocaine. The test solutions are prepared by dissolving the test material in 10% w / v ethanol to deliver an injection volume of 1 ml / kg. All injections are given 15 minutes i. p. before the training and testing sessions. Results: The degree of discriminative stimulus effects of the ethanol / cocaine type is reflected in the percentage of responses during the test sessions in the lever associated with ethanol / cocaine during the training sessions. These values are calculated for each rat and are averaged for the group. As with ethanol / cocaine, ethanol / d, 1 -MPH produces ethanol / cocaine lever response rats in one or more doses that do not decrease response rates compared to those in the brine control test sessions . Ethanol / d, 1 -MPH is equipotent in comparison to ethanol / cocaine for both discriminative effects of stimulus and response rate. Ethanol / d-MP H is half potent compared to ethanol / d, 1 -MPH.

Claims

REIVI NDICATIONS 1 . A method for reducing co-abuse of a methylphenidate drug with a substance presumably causing / -ethylphenidate when ingested in combination with the methylphenidate drug comprising: - identifying a patient or group of patients alleged to abuse or is prone to abusing the combination, and - providing the patient or group of patients with a methylphenidate drug substantially free of l-threo methylphenidate. 2. The method according to claim 1, wherein said substance is ethyl alcohol. 3. The method according to claim 1, wherein said methylphenidate drug is available orally, intravenously, parenterally, by aerosol or gas suspension, or transdermally. 4. The method according to claim 3, comprising up to about 10 mg of methylphenidate drug. The method according to claim 3, comprising up to about 5 mg of methylphenidate drug. 6. The method according to claim 3, comprising up to about 3 mg of methylphenidate drug. The method according to claim 3, comprising from about 0.1 mg to about 1000 mg of methylphenidate drug. 8. The method according to claim 1, wherein said patient has or presumably has ADD or ADH D. 9. A method for reducing co-abuse of a methylphenidate drug with a substance that presumably originates / -ethylphenidate when ingested in combination with the methylphenidate drug which comprises: - identifying a patient or group of patients who presumably abuse or who is prone to abuse the combination; and - decreasing the amount of / -ethylphenidate produced by the ingestion of the combination by making available to said patient or group of patients a methylphenidate drug substantially free of l-threo methylphenidate. The method according to claim 9, wherein said substance is ethyl alcohol. eleven . The method according to claim 9, wherein said methylphenidate drug is available orally, intravenously, parenterally, by aerosol or gas suspension, or transdermally. 12. The method according to claim 1, comprising up to about 10 mg of methylphenidate drug. The method according to claim 1, comprising up to about 5 mg of methylphenidate drug. The method according to claim 1, comprising up to about 3 mg of methylphenidate drug. The method according to claim 1, comprising from about 0.1 mg to about 100 mg of methylphenidate drug. 16. The method according to claim 9, wherein said patient has or presumably has ADD or ADH D. 1 7. A method for reducing co-abuse of the combination of a methylphenidate drug with an addictive substance comprising: - identifying a patient or group of patients who allegedly abuse or who are prone to abuse the combination; and - making available to the patient or group of patients a methylphenidate drug substantially free of l-threo methylphenidate. 18. The method according to claim 17, wherein said substance is cocaine or a derivative of cocaine. The method according to claim 17, wherein said substance is an opioid analgesic. The method according to claim 17, wherein said substance is ethyl alcohol. twenty-one . The method according to claim 17, wherein said substance is an active agent of CNS. 22. The method according to claim 17, wherein said substance is nicotine. 23. The method according to claim 17, wherein said substance is known to produce a psychotropic effect. 24. The method according to claim 17, wherein said methylphenidate drug is available orally, intravenously, parenterally, by aerosol or gas suspension, or transdermally. 25. The method according to claim 24 comprising up to about 10 mg of methylphenidate drug. 26. The method according to claim 24, which comprises up to about 5 mg of methylphenidate drug. 27. The method according to claim 24, comprising up to about 3 mg of methylphenidate drug. 28. The method according to claim 24, comprising from about 0.1 mg to about 1000 mg of methylphenidate drug. 29. The method according to claim 17, wherein said patient has or presumably has ADD or ADH D. SUMMARY Methods for attenuating or eliminating co-abuse of a methylphenidate drug comprising identifying a patient or group of patients allegedly abusing or presumably abusing said methylphenidate drug in combination with a substance known to or presumably causing the effect of / - ethylphenidate or psychotropic when ingested in the combination and which makes available to said patient or group of patients said methylphenidate drug substantially free of l-threo methylphenidate.